JMML tumor cells disrupt normal hematopoietic stem cells by imposing inflammatory stress through overproduction of IL-1 beta

• Type of Material: Article
• Authors: Yuhan Yan, Emory University; Lei Dong, Emory University; Chao Chen, Emory University; Kevin Bunting, Emory University; Qianjin Li, Emory University; Elliot Stieglitz, University of California San Francisco; Mignon L Loh, University of California San Francisco; Cheng-Kui Qu, Emory University
• Language: English
• Date: 2022-01-11
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 by The American Society of Hematology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2021005089
• Title of Journal or Parent Work: BLOOD ADVANCES
• Volume: 6
• Issue: 1
• Start Page: 200
• End Page: 206
• Grant/Funding Information: This work was supported by National Heart, Lung, and Blood Institute grant HL130995 and National Cancer Institute grant CA255831 (C.-K.Q.) and a Winship Cancer Institute Invest$ Pilot grant (C.K.Q.). Y.Y. is a visiting student of the Emory University School of Medicine–Xiangya Hospital Exchange Program. M.L.L. is the Benioff Chair of Children’s Health and the Deborah and Arthur Ablin Endowed Chair for Pediatric Molecular Oncology at Benioff Children’s Hospital.
• Keywords: JUVENILE MYELOMONOCYTIC LEUKEMIA; Life Sciences & Biomedicine; TYROSINE PHOSPHATASE; NICHES; I RECEPTOR; Science & Technology; OF-FUNCTION MUTATION; PTPN11; Hematology; SHP2
• Research Categories: Health Sciences, Oncology

Abstract

Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/1 BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/1 MPN cells produced excessive IL-1b, but not IL-6, T NF-a, IFN-g, IL-1a, or other inflammatory cytokines. Depletion of the IL-1b receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/1/IL-1R2/2 double mutant mice. These findings suggest IL-1b signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.